Novel paradigms for dialysis vascular access: Introduction.

Nonmaturation of new arteriovenous fistulas (AVFs) remains a major barrier to increasing AVF use in hemodialysis patients (1). Our current clinical paradigmviews nonmaturingAVF as a plumbing problem, with efforts directed at augmenting access flow by surgical or percutaneous interventions (2–4). Unfortunately, the very same interventions utilized to salvage immature fistulas also result in vascular injury, which in turn promotes recurrent intimal hyperplasia, rapid re-stenosis, shortened cumulative AVF survival, and the need for frequent interventions to maintain longterm AVF patency for dialysis (5,6). Vascular access research in humans and experimental models reported in the past few years highlights the complex biologic factors involved in AVF nonmaturation. These studies raise the exciting potential of identifying specific pharmacologic interventions to promoteAVFmaturation.A symposium held at the 2012 American Society of Nephrology Kidney Week in San Diego, California, highlighted new paradigms in our understanding of the mechanisms of AVF nonmaturation, and their implications for prevention of this problem. We invited the speakers at that symposium to amplify on their lectures for this Moving Points in Nephrology collection. Our current understanding of the pathogenesis of AVF nonmaturation distinguishes between upstream and downstream events (7). “Upstream events” result in the initial vascular injury, which in turn produces “downstream events” (a biologic response to the initial injury leading to neointimal hyperplasia, stenosis, and ultimately AVF failure) (Figure 1). The initial injury may be caused by surgical injury to the vessels during AVF creation, as well as hemodynamic shear stress near the anastomotic site. The magnitude of vascular injury and the resultant biologic response is likely modified by numerous factors, including genetic predisposition, uremia, and preexisting vascular pathology. Creation of an AVF results in a nonphysiologic condition whereby the low-pressure vein is exposed to the high-pressure artery, resulting in shear stress and vascular injury. The shear stress in a new AVF is not evenly distributed. Rather, it is localized to the juxtaanastomotic region (within approximately 2 cm of the artery-vein anastomosis). Imaging studies of nonmaturing AVF typically demonstrate focal stenosis in the juxta-anastomotic region (2,3). Most vascular surgeons create the anastomosis with a 90° angle between the vein and the artery. Elegant computational modeling of radiocephalic AVF has demonstrated disturbed flow at the swing segment of the vein and in the arterial segment proximal to the anastomosis (8). Moreover, varying the angle of the anastomosis in this model dramatically alters the shear stress. As the angle is decreased from 90° to 30°, there is a progressive decrease in shear stress, whichmay attenuate the vascular injury, neointimal hyperplasia, and development of juxta-anastomotic stenosis (9). The clinical relevance of these experimental findings was supported by a recent observational clinical study, in which changing the anastomotic angle of AVF from 90° to 30° reduced early juxta-anastomotic stenosis from 40% to 10% (10). Similarly, the Optiflow device may decrease vascular injury by fixing the angle at 60° (11). It is unknown whether the shear stress differs between brachiocephalic and radiocephalic AVF, because the former have a considerably lower nonmaturation rate than the latter (12). The article by Dr. Remuzzi amplifies on the relationship between AVF configuration, shear stress, and development of juxta-anastomotic AVF stenosis. Neointimal hyperplasia is the final common pathway in the pathogenesis of juxta-anastomotic AVF stenosis. It develops within 3 weeks in experimental models of AVF (13–16), and has been documented in a small number of hemodialysis patients who underwent surgical revision due to AVF nonmaturation 2–6 months after their initial AVF creation (17,18). Experimental models have evaluated the role of some specific mediators in regulating neointimal hyperplasia after AVF creation. The initial biologic response to injury entails migration of myofibroblasts and smooth muscle cells from the adventitia and media into the intima, leading to subsequent aggressive neointimal hyperplasia (7). Numerous regulators mediate or modulate this biologic response, including cell cycle regulators, cytokines, chemokines, vasoactive molecules, adhesion molecules, and metallic matrix proteinases. For example, heme oxygenase-1 (HO-1) has antiproliferative properties. HO-1 knockout mice exhibit accelerated neointimal hyperplasia of their AVF, highlighting the physiologic role of HO-1 in attenuating neointimal hyperplasia (13). The clinical relevance of these experimental findings was demonstrated by Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama